PROJECT SUMMARY This project aims to determine whether cannabidiol (CBD), a compound derived from the cannabis plant, is effective in treating alcohol use disorder (AUD) in individuals with comorbid posttraumatic stress disorder (PTSD). CBD is currently a medical research focus because it shows promise for treating anxiety and other brain disorders, but does not produce a `high' like other parts of cannabis, has not been shown to be addictive, and is safe, with few or no side effects. AUD, which is one of the most common and most debilitating psychiatric conditions, is often associated with other comorbid psychiatric disorders ? in particular, PTSD: depending on the population studied, 30?60% of individuals with AUD also have PTSD, with high comorbidity rates in military veterans. Evidence from animal models and clinical studies suggests that the negative emotion caused by PTSD symptoms intensifies craving for alcohol during alcohol withdrawal, perpetuating the addictive cycle; further, evidence shows that the brain circuits underlying negative emotion and addiction are linked in a forebrain area called the extended amygdala, which provides a neuropharmacological target to simultaneously treat both negative emotion and alcohol addiction in individuals with AUD and PTSD. CBD is known to inhibit brain activity in the extended amygdala, leading to reduced anxiety in both animal models and humans. CBD also reduces addictive alcohol seeking in animal models. In this project, we aim to test the hypothesis that oral CBD will reduce alcohol drinking in individuals with AUD comorbid with PTSD. To test this hypothesis, 50 otherwise healthy adult participants with moderate or severe AUD and PTSD will be randomized to treatment with either CBD (400 mg per oral daily) or placebo, for a period of 6 weeks, such that both participants and study staff are blind to treatment condition. We will collect baseline and weekly data on alcohol usage and PTSD symptoms, and assess whether CBD treatment leads to a greater improvement in these measures relative to placebo, and whether reduction in alcohol drinking is temporally linked to improvement in PTSD symptoms. Subjects will also participate in a task designed to quantify the psychological and physiological links between negative emotion produced by re-experiencing PTSD trauma, and alcohol craving. The task will be administered at baseline, before treatment, and following 6 weeks of treatment. We will compare the treatment-associated reduction in alcohol craving elicited by trauma-associated negative emotion between CBD and placebo groups. This study will be the first to test whether CBD is effective in treating alcohol addiction and in treating PTSD in humans, and the first to examine the interaction between these treatment effects. Results will serve as proof of concept and provide guidance for a future larger clinical trial. Because CBD is a safe, readily available drug, such a trial would have an immense potential to prevent death, medical illness, and psychological suffering associated with AUD and PTSD. Further, because the brain circuits via which CBD acts to produce hypothesized effects are relatively well-understood, results may substantially advance understanding of the neurobiological basis of alcohol addiction.